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Protein Abundance of Clinically Relevant Drug Transporters in the Human Liver and Intestine: A Comparative Analysis in Paired Tissue Specimens
Author(s) -
Drozdzik Marek,
Busch Diana,
Lapczuk Joanna,
Müller Janett,
Ostrowski Marek,
Kurzawski Mateusz,
Oswald Stefan
Publication year - 2019
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1301
Subject(s) - abcg2 , organic anion transporting polypeptide , transporter , multidrug resistance associated protein 2 , organic anion transporter 1 , ileum , atp binding cassette transporter , multidrug resistance associated proteins , organic cation transport proteins , pharmacology , p glycoprotein , solute carrier family , jejunum , multiple drug resistance , chemistry , small intestine , efflux , monocarboxylate transporter , biochemistry , biology , gene , antibiotics
Bioavailability of orally administered drugs is partly determined by function of drug transporters in the liver and intestine. Therefore, we explored adenosine triphosphate–binding cassette (ABC) and solute carriers family transporters expression (quantitative polymerase chain reaction) and protein abundance (liquid chromatography tandem mass spectrometry ( LC ‐ MS / MS )) in human liver and duodenum, jejunum, ileum, and colon in paired tissue specimens from nine organ donors. The transporter proteins were detected in the liver (permeability‐glycoprotein (P‐gp), multidrug resistance protein ( MRP )2, MRP 3, breast cancer resistance protein ( BCRP ), organic anion‐transporting polypeptide ( OATP )1B1, OATP 1B3, OATP 2B1, organic cation transporter ( OCT )1, OCT 3, organic anion transporter 2, Na+‐taurocholate cotransporting polypeptide, monocarboxylate transporter ( MCT )1, and multidrug and toxin extrusion 1) and the intestine (P‐gp, multidrug‐resistance protein ( MRP )2, MRP 3, MRP 4, BCRP , OATP 2B1, OCT 1, apical sodium–bile acid transporter (only ileum), MCT 1, and peptide transporter ( PEPT 1)). Significantly higher hepatic gene expression and protein abundance of ABCC 2 / MRP 2, SLC 22A1 / OCT 1, and SLCO 2B1 / OATP 2B1 were found, as compared to all intestinal segments. No correlations between hepatic and small intestinal protein levels were observed. These observations provide a description of drug transporters distribution without the impact of interindividual variability bias and may help in construction of superior physiologically based pharmacokinetic and humanized animal models.